title: Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential.
abstract: Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
authors.affiliation: Experimental Cardiovascular Medicine, Bristol Heart Institute, UK.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Katare
authors.forename: Mauro
authors.initials: M
authors.lastname: Siragusa
authors.forename: Luciola S
authors.initials: LS
authors.lastname: Barcelos
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mangialardi
authors.forename: Orazio
authors.initials: O
authors.lastname: Fortunato
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tran
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wojakowski
authors.forename: Iwona
authors.initials: I
authors.lastname: Mroz
authors.forename: Andrew
authors.initials: A
authors.lastname: Herman
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.forename: Jean Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Raimondo
authors.initials: R
authors.lastname: Ascione
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000787:Angina Pectoris / Q000503:physiopathology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology / Q000637:transplantation*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin